Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors

Abstract

Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel. Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m 2 , respectively. After increasing paclitaxel to 175 mg/m 2 , the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle. Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m 2 paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m 2 , and 438 mg/m 2 was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 F 0.24 h) and a low steady-state apparent volume of distribution (25.1 F 8.1L/m 2 ). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose. Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.

Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells

“…In a phase I clinical trial of elesclomol in combination with paclitaxel for patients with refractory solid tumors, elesclomol was well tolerated and did not increase toxicity [31]. We showed that elesclomol had no cytotoxicity in normal breast epithelial cells, consistent with the results from clinical trials [1,2].…”

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…Many developmental redox therapeutics have shown a potentiating effect on pharmacodynamic activity of other anticancer agents and radiation, but offer only modest or no chemotherapeutic benefit if used as single agents (9,29,193). Therefore, many ongoing clinical studies test activity of these agents as combinatorial drugs, consistent with the mechanism of action that involves induction of deviations from redox homeostasis that preferentially sensitize cancer cells to the cytotoxic effects of chemotherapeutic agents (9,29,232,246,288). However, other ongoing studies examine feasibility of single agent redox chemotherapy as detailed throughout this review.…”

“…4-38), a symmetric thiobenzoylhydrazide-derivative [Nmalonyl-bis (N 0 -methyl-N 0 -thiobenzoylhydrazide, STA-4783), was originally derived from a differential phenotypic screen that assessed potentiation of in vitro cytotoxicity of paclitaxel against human tumor cell lines (29,118,193). Early preclinical studies indicated that the growth of human tumor xenografts in CD-1 nude mice was unaffected by treatment with elesclomol administered as single therapeutic agent (7,25,26).…”

Overcoming Immunologic Tolerance to Melanoma: Targeting CTLA-4 with Ipilimumab (MDX-010)

“…Another compound under investigation for use in metastatic melanoma is STA-4783, which has been found to dramatically enhance the antitumor activity of paclitaxel without increasing host toxicity [38]. STA-4783 is a bisthiobenzoylhydrazide compound and an inducer of heat shock proteins.…”